The present study was designed to compare the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) with data from forearm metabolic studies of healthy individuals and of subjects in various pathological states. Fifty-five healthy individuals and 112 patients in various pathological states, including type 2 diabetes mellitus, essential hypertension and others, were studied after an overnight fast and for 3 h after ingestion of 75 g of glucose, by HOMA, QUICKI and the forearm technique to estimate muscle uptake of glucose combined with indirect calorimetry (oxidative and non-oxidative glucose metabolism). The patients showed increased HOMA (1.88 ± 0.14 vs 1.13 ± 0.10 pmol/l x mmol/l) and insulin/glucose (I/G) index (1.058.9 ± 340.9 vs 518.6 ± 70.7 pmol/l x (mg/100 ml forearm) -1 ), and decreased QUICKI (0.36 ± 0.004 vs 0.39 ± 0.006 (µU/ml + mg/dl) -1 ) compared with the healthy individuals. Analysis of the data for the group as a whole (patients and healthy individuals) showed that the estimate of insulin resistance by HOMA was correlated with data obtained in the forearm metabolic studies (glucose uptake: r = -0.16, P = 0.04; non-oxidative glucose metabolism: r = -0.20. P = 0.01, and I/G index: r = 0.17, P = 0.03). The comparison of QUICKI with data of the forearm metabolic studies showed significant correlation between QUICKI and non-oxidative glucose metabolism (r = 0.17, P = 0.03) or I/G index (r = -0.37, P < 0.0001). The HOMA and QUICKI are good estimates of insulin sensitivity as data derived from forearm metabolic studies involving direct measurements of insulin action on muscle glucose metabolism.
Insulin-dependent type I diabetes mellitus (IDDM) is caused by autoimmune destruction of pancreatic β-islet cells mediated by inflammatory T cells. The pathogenic process evolves gradually for several years and becomes symptomatic when most Langerhans islands are destroyed. Antibodies against β-cell antigens (like anti-glutamic acid decarboxylase, GAD) are markers of the autoimmune reaction and levels of proinsulin C-peptide correlate with endogenous insulin secretion. Several immunosuppressive regimens have demonstrated clinical and laboratorial benefit in early onset IDDM, presumably sparing islets reserve, but most responses were transient and long term toxicity limited their continuous use. In view of durable remissions observed in various autoimmune diseases treated with high-dose immunosuppression and autologous hematopoietic stem cell transplantation (AHSCT), we started in December/03 a phase I/II trial of AHSCT in early-onset IDDM. Patients from 12–35 years old with <6 weeks from diagnosis have their peripheral blood stem cells mobilized with 2 g/m2 cyclophosphamide and 10 mcg/kg G-CSF, cryopreserved and reinfused (>2 million/kg) after conditioning with 200 mg/kg cyclophosphamide and 4,5 mg/kg rabbit antithymocyte globulin- ATG (Thymoglobuline, SangStat). End points of the study are insulin needs (U/kg/d), glycosilated hemoglobin levels, anti-GAD titers and C-peptide levels. Four patients have been transplanted and the insulin usage of the first three patients is shown in the Figure. The first patient received high dose of steroids to prevent ATG hypersensitivity and showed increasing needs of insulin after mobilization. The other two patients received minimal (#2) or no (#3) steroid dose during conditioning and showed decreasing needs of insulin after mobilization (Figure). Patient #2 presented bilateral pneumonia while pancytopenic, recovered after treatment with antibiotics and Amphotericin-B but did not require insulin therapy. A fourth patient has just been discharged from the BMT Unit. Immunologic studies in the three patients with longer follow-up showed a progressive shift from Th1 to Th2 cytokine profile after transplantation which could provide a mechanism for the modulation of the autoimmune process by high dose immunosuppression and autologous HSC. In conclusion, the preliminary results are encouraging but must be validated with a larger number of patients (12 planned in this phase) and a longer followup (5 years). Figure Figure
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